Tuberculosis (TB) and problems associated with its treatment. TB is one of the leading human infectious diseases caused by the bacterium Mycobacterium tuberculosis (M. tb). It remains a major world-wide public health problem and continues to pose a serious threat to the global population, especially in third-world countries. According to the WHO, TB incidence and prevalence were estimated to be 8.8 and 12 million cases respectively, in 2010. 1.45 million, which includes 1.1 million among HIV-negative and 0.35 million among HIV-positive, people died from TB in the same year. Tuberculosis and HIV co-infection is one of the current major challenges in the control of TB, since HTV infection increases the risk of developing active TB. Most importantly, one-third of the world population has latent TB infection and 10% of those infected people will develop active TB at some point during their life time. Furthermore, multi drug-resistant (MOR) TB has become increasingly prevalent, and extremely drug-resistant (XOR) and totally drug-resistant (TOR) forms of TB are also emerging posing a major threat to progress in global TB control. Only 1% of patients with MOR-TB are estimated to be on appropriate drug treatment, with predicted poor treatment outcomes. The existence of chronic diseases such as diabetes is known to increase the risk of developing active TB by 3-fold. All of these situations together highlight an urgent need of new drugs with novel mechanisms of action, especially for the effective management of MOOR—, XOR— and TOR TB.
The focus of anti-TB drug development has always been on regimens rather than on single drugs to reduce the risk of development of resistance given the duration of therapy. Such regimens should include new drugs with novel mechanisms of action that do not demonstrate cross-resistance to current first- and second line TB drugs. An ideal drug combination should consist of at least three drugs that are bactericidal against both susceptible and resistant strains of M. tb, and have potent, complementary and synergistic activities against various subpopulations of M. tb (notably persisters). This combination should produce a stable cure in a much shorter period of time than the current prolonged treatment of 6 months to 2 years. Additionally, such a novel combination should be useful for the treatment of patients with M. tb and HIV co-infection such that the drug interactions with antiretroviral drugs are limited avoiding the current removal of rifampicin from the regimen. However, the need for multiple drugs taken simultaneously and for a long duration can cause toxicity and result in poor patient compliance.
Apart from nearly-approved drugs (or drugs at the final stage of clinical development) such as gatifloxacin, moxifloxacin and linezolid, there are approximately 11 compounds in different phases of clinical trials for TB. They are: PA-824 (a nitroimidazole), OPC-67683 (a nitroimidazole), PNU-100480 (an oxazolidinone), AZD5847 (an oxazolidinone), SQ609 (a diamine derivative), SQ109 (a diamine derivative), DC-159a (a fluoroquinolone), TMC207 (a diarylquinoline), BTZ043 (a nitrophenyl derivative), DNB 1 (a nitrophenyl derivative), and BDM31343 (an oxadiazole derivative). New targets of some of them have also been identified. Of note, the most promising anti-TB drug compound, TMC207, was found to be a mycobacterial ATP synthase inhibitor, and this target was found using the approaches described in this proposal. Thus, strategies for the development of new anti-TB drugs are ready to fuel the existing pipeline of TB drug regimens. However, despite progress so far, the global drug TB pipeline is still grossly insufficient to address unmet treatment needs, particularly with regard to providing novel, short course, and safe drugs that are effective against drug resistant TB.
Drug screening procedures. Recent advances in biochemistry and genetics have offered screening of drug molecules by a target-based approach. However, this approach has had little success in the anti-bacterial drug discovery area in general. The essential nature of a target for bacterial replication may be a prerequisite but it does not ensure its druggability; for many essential targets it has not been possible to identify specific inhibitors with drug-like properties. For example, several high-throughput screening projects for identifying inhibitors of isocitrate lyase, a key glyoxylate-shunt-pathway enzyme found to be essential for mycobacterial intracellular growth and their long-term persistence in mice, were discontinued due to the lack of druggability of this target. Although not absolutely free of drawbacks, whole bacterial cell-based phenotypic screening approaches have been proven to be a more successful strategy for identifying new drug candidates. Such a strategy recognizes the potential holistic interactions of a drug target(s) with one or more components in a bacterial cell and defines its essentiality in a more physiologically relevant manner. One of the recent successes with the whole cell-screening approach has been the identification of the potent new TB drug candidate diarylquinoline (TMC207).
Screening for anti-TB drugs should not be limited to compound libraries based solely on anti-bacterial targets, but rather should be extended to other classes of libraries based on eukaryotic or mammalian targets for the creation of successful drug regimens. For example, two anti-psychotic drug molecules phenothiazine and diarylquinoline (TMC207) have been shown to possess potent anti-TB activities upon re-purposed screening. A bicyclic nitroimidazofuran compound, PA-824, which had been investigated as a potential radio-sensitizing agent for use in cancer radiotherapy, was later found to display anti-TB activities in both in vitro and in vivo models. While some need TB drug candidates are being identified, there still remains a need for the identification of additional drugs for use in treating this difficult to treat disease.